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Fluoride and Thyroid Function
Fluoride at low levels disrupts thyroid function, according to a 2006 National Research Council (NRC) report and more recent studies. Fluoride accumulates in the thyroid and produces morphological changes. Numerous animal experiments show that high fluoride consumption reduces thyroid hormone levels (T3 and T4) and increases thyroid-stimulating hormone (TSH) levels. In addition, fluoride has other adverse endocrine effects, including impaired glucose tolerance and earlier sexual maturation. Subclinical thyroid dysfunction increases the risk of heart disease, cognitive dysfunction, depression, and bone demineralization (in the case of hyperthyroidism). These effects occur at levels far below those needed to produce dental fluorosis (discoloration and pitting in tooth enamel), which is the most recognized adverse effect.
Since the 2006 NRC report, researchers have learned more about fluoride's effect on thyroid function. Fluoride does not compete with iodine for transport into the thyroid, according to the NRC report. It does, however, inhibit the activity of Na+/K-ATPase (the enzyme needed to fuel the cellular sodium-potassium pump) and thyroid peroxidase (the enzyme that catalyzes thyroid hormone from thyroglobulin), according to more recent investigations.
In their 2013 study, Swati Singla and Shashi Aggarwal reported correlations between fluoride content of drinking water and abnormal thyroid peroxidase (TPO) and thyroid hormone levels. The Indian researchers compared 633 people with hypothyroidism and fluorosis, 227 people with hyperthyroidism and fluorosis, and 140 age- and sex-matched controls. Fluorosis and thyroid dysfunction are major problems in India. Drinking water used by the fluorotic patients had a fluoride content that ranged from 1.01 to 16.00 mg/L. Drinking water for the control group contained 0.76 to 1.00 mg/L fluoride. The US Maximum Contaminant Level Goal for fluoride in drinking water is 4.00 mg/L. (Fluoride is an industrial pollutant.)
The researchers grouped the fluorotic thyroid patients according to the level of fluoride in their drinking water. All of them had significantly higher fluoride blood levels than the nonfluorotic control group. Their urinary iodine and fluoride concentrations were higher as well. Those whose drinking water contained 1.01 to 4.00 mg/L excreted the highest concentration of fluoride in their urine (3.68 ± 0.53 mg/L). As drinking water fluoride levels increased, less fluoride and more iodine were excreted. Singla and Aggarwal found that TPO activity in the hyperthyroid and the hypothyroid groups decreased significantly as fluoride exposure increased. Thyroid hormone levels (T3, T4) also decreased with increased fluoride exposure and TSH levels rose.
The 2006 NRC chapter summary on fluoride's endocrine effects says: "'In humans effects on thyroid function were associated with fluoride exposures of 0.05-0.13 mg/kg/day when iodine intake was adequate and 0.01-0.03 mg/kg/day when iodine intake was inadequate. ..." Robert J. Carton, PhD, a retired environmental scientist, noted in his review of the 2006 report: "This simply means for a 70-kg person (often called the 'standard man'), fluoride doses as low as 3.5 mg/day for those with an adequate intake of iodine, and 0.7 mg/day for those with an inadequate intake of iodine may have an effect on the thyroid." Many Americans consume more than 0.7 mg/day via food alone.
No research study claims that fluoride is the sole cause of thyroid dysfunction, but excessive fluoride is clearly a largely unexamined – and preventable – contributor.
Carton RJ. Review of the 2006 United States National Research Council Report: Fluoride in Drinking Water. Fluoride. July–September 2006;39(3):163–172. Available at www.khi.org. Accessed November 25, 2015.
National Research Council. Fluoride in Drinking Water – A Scientific Review of EPA's Standards. Washington, DC: The National Academies Press; 2006. Available at www.nap.edu/read/11571/chapter/1. Accessed November 25, 2015.
Singla S, Aggarwal S. Thyroid peroxidase activity as toxicity target for fluoride in patients with thyroid dysfunction. Curr Res Microbiol Biotechnol. 2013;1(2):53–57. Available at http://crmb.aizeonpublishers.net/content/2013/2/crmb53-57.pdf. Accessed November 25, 2015.
Maternal Stress and Epigenetics
Posttraumatic stress disorder (PTSD) produces epigenetic changes in glucocorticoid-related (e.g., NR3C1) and FKBP5 genes that are transmitted to an affected woman's offspring. Babies born to women with PTSD have lower cortisol levels and increased glucocorticoid receptor sensitivity, indicating decreased resilience to stress and increased susceptibility to developing PTSD when exposed to traumatic events. A 2014 study led by Nadir Perroud found that women who were exposed to the Tutsi genocide during pregnancy and their offspring had lower cortisol and glucocorticoid receptor levels than nonexposed women with the same ethnicity and time of pregnancy and their children. The researchers also report an association between PTSD and NR3C1epigenetic modifications found in exposed mothers and their children. They say that these changes "may underlie the possible transmission of biological alterations of the [hypothalamic-pituitary-adrenal] axis."
Neuroscientist Rachel Yehuda, PhD, and colleagues began investigating the effect of parental PTSD on offspring in the late 1990s. They performed a series of studies involving the offspring of Holocaust survivors. Offspring with at least one parent with PTSD "displayed low urinary and plasma cortisol levels, and increased glucocorticoid responsiveness as measured by plasma cortisol levels in response to low dose dexamethasone administration [a test to assess adrenal function]," compared with those whose parents did not have PTSD. When Yehuda and colleagues compared Holocaust survivor offspring with demographically matched Jewish controls whose parents were not exposed to trauma, they found "a greater prevalence of PTSD among offspring with maternal PTSD." The highest rate of PTSD was found when both parents had PTSD. Paternal PTSD alone was associated with anxiety disorders.
Some PTSD-associated epigenetic changes were reversed in military veterans who responded to 12 weeks of psychotherapy in a small 2013 study. Higher levels of glucocorticoid receptor (GR) gene promoter methylation at pretreatment (indicating lower GR expression) were associated with a positive response to psychotherapy treatment. Although GR gene expression did not change in treatment responders, FKBP5 (a mineralocorticoid receptor gene linked to PTSD) expression did; FKBP5 promoter methylation decreased, indicating greater FKBP5 gene expression. In addition, plasma and urinary cortisol levels indicated decreased GR sensitivity. "These findings distinguish two seemingly stable epigenetic markers that may associate, respectively, with prognosis (GR gene methylation) and symptom severity (FKBP5 gene methylation)," say the authors. In addition, this study indicates that glucocorticoid-related genes respond to environmental factors – including psychotherapy – throughout life.
This small 2013 study needs to be replicated. Still, it offers hope that epigenetic stress responses passed from mother to child can be mitigated.
Perroud N, Rutembesa E, Paoloni-Giacobina A, et al. The Tutsi genocide and transgenerational transmission of maternal stress: epigenetics and biology of the HPA axis [abstract]. World J Biol Psychiatr. 2014;15(4):334–345. Available at http://www.ncbi.nlm.nih.gov/pubmed/24690014. Accessed November 25, 2015.
Yehuda R, Bell A, Bierer LM, Schmeidler J. Maternal, not paternal PTSD, is related to increased risk for PTSD in offspring of Holocaust survivors. J Psychiatr Res. October 2008;42(13):1104–1111. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2612639. Accessed November 25, 2015.
Yehuda R, Daskalakis NP, Desarnaud F, et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry. 2013;4:118. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3784793. Accessed November 25, 2015.
Yehuda R, Flory JD, Bierer LM, et al. Lower methylation of glucocorticoid receptor gene promoter if in peripheral blood of veterans with posttraumatic stress disorder [abstract]. Biol Psychiatr. February 15, 2015;77(4):356–364. Available at www.biologicalpsychiatryjournal.com/article/S0006-3223%2814%2900100-0/abstract. Accessed November 25, 2015.
Prenatal Genetic Testing Lawsuits
Malpractice lawsuits against practitioners and medical laboratories that offer prenatal genetic tests are on the rise. Parents faced with caring for a newborn with a debilitating, inheritable disease have won large settlements when practitioners failed to inform parents about available prenatal genetic tests that would have identified the condition prebirth, giving the parents the option of terminating the pregnancy. Judgments or settlements have also resulted when medical laboratories mistakenly informed parents that their unborn child was free of a screened-for inheritable disease, such as cystic fibrosis. In both cases, the lack of accurate genetic test results led to the birth of a child with a painful, incurable, and financially devastating disease. The large settlements help with the child's medical and living costs.
Although some state legislators focus on the morality of abortion implicit in these "wrongful birth lawsuits," judges and plaintiffs' attorneys view these cases as examples of medical negligence and malpractice.
McLeod PS. Clinical pathology laboratories should be aware of new malpractice risks from genetic testing [online article]. DARK Daily. July 25, 2012. Available http://www.darkdaily.com/clinical-pathology-laboratories-should-be-aware-of-new-malpractice-risks-from-genetic-testing-71512. Accessed November 25, 2015.
Thyroid Cancer Overdiagnosis
"There is an ongoing epidemic of thyroid cancer in the United States. The epidemiology of the increased incidence, however, suggests that it is not an epidemic of disease but rather an epidemic of diagnosis," according to Louise Davies, MD and H. Gilbert Welch, MD. Thyroid cancer incidence has almost tripled since 1975 (4.9 to 14.3 per 100,000) – primarily due to increased detection of papillary thyroid cancers. These small, nonaggressive cancers are common in people who display no symptoms during their lifetime and who die from causes other than thyroid cancer. Despite increased detection, death rate from thyroid cancer has not decreased, which indicates overdiagnosis.
For their 2014 study, Davies and Welch used 1975–2009 data from nine SEER (Surveillance, Epidemiology, and End Results program) areas and thyroid cancer mortality data from the National Vital Statistics System, which contains cause-of-death listed on death certificates. They found higher cancer detection rates among women compared with men: "The absolute increase in thyroid cancer in women (from 6.5 to 21.4 = 14.9 per 100,000 women) was almost 4 times greater than that of men (from 3.1 to 6.9 = 3.8 per 100000 men)." They also found that the thyroid cancer mortality rate has remained stable at about 0.5 deaths per 100,000.
Davies and Welch dispute the idea that the stable mortality rate is the result of treatment improvements. "For this explanation to be true," they write, "the improvements in treatment would have had to exactly offset the rise in incidence. If treatment improved too fast, the mortality line would fall. If treatments improved too slowly, the mortality line would rise. While this explanation is theoretically possible, it is not particularly plausible in explaining 30 years of stable mortality." The stable mortality rate suggests that many thyroid tumors pose no threat to life. Other evidence for overdiagnosis stems from data showing that access to medical care is directly related to thyroid cancer detection: "People with enhanced health care access tend to have not only more small cancers identified but also more thyroid cancers identified overall."
A 2015 study from Memorial Sloan Kettering Cancer Center, using data from 1950 to 2005, supports the observation that thyroid cancer survival rates have remained stable despite an increase in diagnosis. The MSKCC study also found that incidence rates of large tumors (>6 cm) and metastasis have not changed over time. The authors say that improved survival rates in recent years are due to the increased number of small, asymptomatic thyroid cancers that are being detected and treated. "Relying on survival rates to measure success in treating thyroid cancer may reinforce inappropriately aggressive management," they write. "Treatment decisions in thyroid cancer should be made based on mortality, not survival data."
Total thyroidectomy is the usual treatment for thyroid cancer, subjecting patients to risk of complications such as permanent hypoparathyroidism and vocal cord paralysis. In addition, patients require thyroid hormone therapy and monitoring for the rest of their lives when the thyroid is removed. After surgery, half of the patients also receive radiation treatment, usually in the form of radioactive iodine. Radioactive iodine is associated with increased risk of leukemia and other secondary cancers. "These aggressive therapies persist despite guidelines suggesting that partial thyroidectomy is a reasonable approach for lower risk cancers and data indicating that few patients with papillary thyroid cancer derive survival benefit from radioactive iodine," say Davies and Welch.
Davies and Welch offer several suggestions for reducing aggressive treatment of small, asymptomatic thyroid cancers. Active surveillance, an option for nonaggressive prostate cancers, is now being investigated at MSKCC and in Japan. In addition to this wait-and-see treatment approach, Davies and Welch suggest reclassifying small thyroid neoplasms with a term other than cancer, an idea that has been suggested for ductal carcinoma in situ breast neoplasms, another condition that typically leads to unnecessarily aggressive treatment. In the meantime, practitioners need to share the uncertainties surrounding small thyroid cancers and their treatment. Davies and Welch also ask clinicians to be aware of the hazards involved in "looking too hard for thyroid cancer." "Patients – and in the case of thyroid cancer, particularly women – need protection not only from the harms of unnecessary treatment but also the harms of unnecessary diagnosis," they write.
Davies L, Welch HG. Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014;140(4):317–322. Available at http://archotol.jamanetwork.com/article.aspx?articleid=1833060. Accessed November 25, 2015.
Ho AS, Davies L, Nixon IJ, et al. Increasing diagnosis of subclinical thyroid cancers leads to spurious improvements in survival rates [abstract]. Cancer. June 1, 2015;121(11):1793–1799. Available at www.ncbi.nlm.nih.gov/pubmed/25712809. Accessed November 25, 2015.
Vaccines During Pregnancy
In November 2015, FDA announced recommendations for licensing vaccines intended for use during pregnancy to prevent disease in the infant. No vaccines have FDA approval for use during pregnancy at this time, even though the CDC has recommended tetanus, diphtheria, and acellular pertussis (Tdap) vaccination during pregnancy since 2011. The rationale for the CDC recommendation is to decrease whooping cough risk in infants. (CDC also recommends flu vaccinations during pregnancy.)
Tdap vaccines Adacel (Sanofi Pasteur) and Boostrix (GlaxoSmithKline) are licensed for use in adults and older children. The manufacturer inserts for both products (available at http://www.immunize.org/packageinserts/pi_tdap.asp) state that the vaccines have not been evaluated for fetal harm or reproductive adverse effects in humans and that the vaccines "should be given to a pregnant woman only if clearly needed." Neither manufacturer knows if the vaccines are transmitted in human milk. FDA licensure means that product labeling would contain information for its safe and effective use, information that is currently lacking.
The FDA Briefing Document lists several concerns that manufacturers should address in order to license a vaccine for use during pregnancy. Adverse effects may be caused by vaccine antigens, the adjuvants and excipients used to enhance vaccine effects, and/or a mother's immune response. Pregnancy makes a woman's immune system less sensitive in order to tolerate the growth of the fetus. Vaccination incites an inflammatory reaction that "could disturb maternal mechanisms that maintain tolerance of foreign fetal antigens, potentially leading to adverse pregnancy outcomes, such as spontaneous abortion or intrauterine growth restriction or preterm birth," according to the FDA.
Detecting adverse effects can be tricky, since first trimester miscarriages, preterm births, deep vein thrombosis, and other events occur fairly often in pregnant women. Identifying safety concerns requires well-designed, controlled studies with inert placebos, such as saline. Most vaccine safety studies use the vaccine formula (containing toxic aluminum compounds, formaldehyde, and other constituents) minus the antigen as a control, or the studies compare two types of vaccines or vaccine doses/schedules.
I found on PubMed just one blinded Tdap safety study for pregnancy use that used a saline placebo. The February 2015 study led by Flor M. Munoz was, in the authors' own words, an "exploratory study that was not powered to test any specific hypotheses." Just 33 women received Tdap while pregnant (30–32 weeks), and 15 received a saline injection at the same point in their pregnancies. After delivery, treatment was switched; women who had received the placebo were given Tdap, and the vaccinated women received the saline injection.
The authors state, "There were no differences in the infants' growth and development (Tables S2 and S3), and no cases of pertussis illness occurred in mothers or infants." Considering that the incidence of whooping cough in US babies under 1 year peaked at just over 120 per 100,000 (according to CDC), it would have been surprising if pertussis had shown up. I also question the assertion that infants showed no differences in development. Growth measures were very similar, but I noticed some differences in test results for the Bayley-III developmental screening test, which was administered to infants at 13 months. Bayley-III screens receptive and expressive communication, fine and gross motor skills, and cognition. I was troubled that the body of the article made no mention that a noticeably lower percentage of the treated infants scored "competent" in four of the five categories. For example, 63.3% of babies from vaccinated mothers compared to 78.6% of control babies were assessed competent in gross motor development (sitting, crawling, standing, and walking unassisted). Receptive communication was the exception; a smaller percentage of the control group (64.3%) received competent scores for receptive communication compared with the treated group (70.0%).
The difference between the two groups was not statistically significant; this study did not have enough participants for any definite conclusions to be made. Still, I would expect a safety study to make some comment about the need for follow-up research. Instead, the authors concluded: "Until further research provides definitive evidence of the safety and efficacy of Tdap immunization during pregnancy, our findings support current ACIP recommendations to immunize pregnant women with Tdap during pregnancy to protect infants against pertussis."
Only a few vaccine trials posted at www.clinicaltrials.gov are designed to investigate safe vaccine use during pregnancy. Study designs make me question their usefulness in assessing the safety risks for women and their babies. A Vanderbilt University observational study on TDAP Safety in Pregnant Women (NCT 02209623) has no placebo control. A Mexican study (NCT 01445743) does have a saline control, but the sole outcome being measured is the antibody levels in infants. No studies test the cumulative effects of vaccines despite the recognized toxic effects of vaccine constituents such as aluminum compounds, formaldehyde, and the surfactant polysorbate-80. A list of excipients and adjuvants is available at CDC http://www.cdc.gov/vaccines/vac-gen/additives.htm (see Reference Materials).
FDA Vaccines and Related Biological Products Advisory Committee Meeting. Clinical development and requirements for licensure of vaccines intended for use during pregnancy to prevent disease in the infant [online document]. November 13, 2015. Available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/
VaccinesandRelatedBiologicalProductsAdvisoryCommittee/ucm427602.htm. Accessed November 25, 2015.
Jackson BJ, Needelman H., Roberts H, Willet S, McMorris C. Bayley Scales of infant development screening test-gross motor subtest: efficacy in determining need for services. Pediatr Phys Ther. Spring 2012;24(1):58–62. Available at http://journals.lww.com/pedpt/Fulltext/2012/24010/Bayley_Scales_of_Infant_Development_Screening.12.aspx. Accessed January 7, 2016.
Mahoney D. CDC panel expands Tdap vaccine in pregnancy recommendation [online article]. Medscape Medical News. October 24, 2012. http://www.medscape.com/viewarticle/773230. Accessed November 25, 2015.
Munoz FM, Bond NH, Maccato M, et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1760–1769. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333147. Accessed January 3, 2015.
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